The occurrence and relative activities of the major pathways for pyrimidine metabolism in extrahepatic tissues have not been clearly established and the major source of the pyrimidine nucleotides utilized by these tissues remains uncertain. Accordingly, we propose an investigation with the following specific aims: 1. A comparison of the activity of the orotate pathway for the de novo biosynthesis of pyrimidines in slices of the liver and extrahepatic tissues of the rat and human. 2. A comparison of the activity of the salvage and catabolic pathways of pyrimidine metabolism in slices of the liver and extrahepatic tissues of the rat and human. 3. A study of changes in the activity of the de novo and salvage pathways in response to an increased demand for pyrimidines through the stimulation of tissue growth and metabolism. 4. An investigation of the dependency of extrahepatic tissues on the liver for a supply of preformed pyrimidines. 5. A study of the tissue distribution and operation of the feedback control of the de novo biosynthesis of pyrimidines by end-product inhibition. 6. A comparative study of pyrimidine metabolism and its regulation in normal and malignant human tissues.